Wei Gong-Hong, Dong Dandan, Zhang Peng, Liu Mengqi, Wei Yu, Wang Zixian, Xu Wenjie, Zhang Qixiang, Zhu Yao, Zhang Qin, Yang Xiayun, Zhu Jing, Wang Liang
Fudan University Shanghai Cancer Center & MOE Key Laboratory of Metabolism and Molecular Medicine and Department of Biochemistry and Molecular Biology of School Basic Medical Sciences, Shanghai Medi.
Shanghai Medical College of Fudan University.
Res Sq. 2024 Apr 4:rs.3.rs-3943095. doi: 10.21203/rs.3.rs-3943095/v1.
Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, a novel oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.
全基因组关联研究（GWAS）已确定了许多与前列腺癌相关的风险位点，但其功能意义仍难以阐明。利用我们的高通量单核苷酸多态性测序（SNPs-seq）方法，我们在多血统GWAS发现的2p25位点内确定rs4519489为潜在的功能性单核苷酸多态性，因为其在蛋白质结合方面存在显著的等位基因差异。在此，我们使用不同的队列数据和实验模型对rs4519489及其相关基因NOL10进行了全面分析。临床研究结果显示，rs4519489基因型与NOL10表达对前列腺癌的预后和严重程度具有协同作用。通过无偏蛋白质组学筛选，我们发现rs4519489的风险等位基因A与USF1（一种与前列腺癌进展和预后相关的新型致癌转录因子）的结合增强，导致NOL10表达升高。此外，我们阐明NOL10调节细胞周期途径，促进前列腺癌进展。NOL10和USF1的同时表达与侵袭性前列腺癌特征和较差的预后相关。总体而言，我们的研究提供了一种通过高通量SNPs-seq和无偏蛋白质组学进行功能性单核苷酸多态性筛选和转录因子鉴定的强大策略，突出了rs4519489-USF1-NOL10调控轴作为前列腺癌临床诊断和治疗的有前景的生物标志物或治疗靶点。
